title: Chemical suppression of an oncogenic splicing variant of AIMP2 induces tumour regression.
abstract: AIMP2 (aminoacyl-tRNA synthetase-interacting multifunctional protein 2) is a potent tumour suppressor that induces apoptosis in response to various oncogenic signals. AIMP2-DX2, an exon2-deleted splicing variant of AIMP2, is up-regulated in lung cancer and competitively suppresses the pro-apoptotic activity of AIMP2, resulting in tumorigenesis. In the present study we report that BC-DXI01, a synthetic compound, specifically reduces the cellular levels of AIMP2-DX2 through selective degradation of the AIMP2-DX2 mRNA transcript. We found that BC-DXI01-mediated cell death positively correlates with AIMP2-DX2 expression in the lung cancer cell lines tested. Administration of BC-DXI01 in a AIMP2-DX2-driven tumour xenograft mice model led to reduced tumour sizes and volumes of up to 60% in comparison with vehicle-treated mice group, consistent with decreases in AIMP2-DX2 transcript and protein levels. Taken together, our findings suggest that tumorigenic activity of AIMP2-DX2 can be controlled by the small chemical BC-DXI01, which can selectively suppress the AIMP2-DX2 mRNA transcript.
authors.affiliation: Medicinal Bioconvergence Research Center, Seoul National University, Seoul 305-343, Korea.
authors.forename: Hee Sook
authors.initials: HS
authors.lastname: Lee
authors.forename: Dae Gyu
authors.initials: DG
authors.lastname: Kim
authors.forename: Young Sun
authors.initials: YS
authors.lastname: Oh
authors.forename: Nam Hoon
authors.initials: NH
authors.lastname: Kwon
authors.forename: Jin Young
authors.initials: JY
authors.lastname: Lee
authors.forename: Doyeun
authors.initials: D
authors.lastname: Kim
authors.forename: Song-Hwa
authors.initials: SH
authors.lastname: Park
authors.forename: Jong-Hwan
authors.initials: JH
authors.lastname: Song
authors.forename: Sunkyung
authors.initials: S
authors.lastname: Lee
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Han
authors.forename: Bum-Joon
authors.initials: BJ
authors.lastname: Park
authors.forename: Jongkook
authors.initials: J
authors.lastname: Lee
authors.forename: Sunghoon
authors.initials: S
authors.lastname: Kim
mesh_terms: D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009687:Nuclear Proteins; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012074:Remission Induction; D023041:Xenograft Model Antitumor Assays; D062366:para-Aminobenzoates / Q000494:pharmacology*
chemical_list: C575685:AIMP2 protein, human; D000813:Anilides; D000970:Antineoplastic Agents; C584113:BC-DXI01; D002352:Carrier Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D062366:para-Aminobenzoates